The present invention relates to a method of preparing alkylated salicylamides from salicylamides. The alkylated salicylamides prepared by this method are suitable for use in compositions for delivering active agents via oral or other routes of administration to animals.
Carsalam (2H-1,3-benzoxazine-2,4(3H)-dionc) is known in the art as an analgesic (see Merck Index, 12th edition, #1915).
Alkylated salicylamides, such as those disclosed in U.S. Pat. No. 5,650,386, have been found to be highly effective as delivery agents for active agents, particularly for oral administration of active agents. Typically, these alkylated salicylamides are prepared by modifying an amino acid or an ester thereof. For example, these alkylated salicylamides may be prepared by acylation of an amino acid or an ester thereof with agents having a leaving group, such as a halogen, carbonyl group, or sulfonyl group, and an appropriate radical to yield the desired modification in the final product. See, for example, U.S. Pat. No. 5,650,386.
Alternate methods of producing alkylated salicylamides would be useful, especially where raw materials are expensive, yields are low, and/or reaction conditions are difficult.
Therefore, there is a need for simpler and less expensive methods of preparing alkylated salicylamides.
The present invention relates to a method of preparing an alkylated salicylamides from a protected and activated salicylamide (hereinafter referred to as a xe2x80x9cprotected/activated salicyamidexe2x80x9d). The method comprises the steps of (a) alkylating the protected/activated salicylamide with an alkylating agent to form a protected/activated alkylated salicylamide and (b) deprotecting and deactivating the protected/activated alkylated salicylamide, simultaneously or in any order, to form the alkylated salicylamide. The alkylated salicylamides prepared by this method are suitable for use in compositions for delivering active agents via oral or other routes of administration to animals.
The term xe2x80x9cprotected salicylamidexe2x80x9d is defined herein as a salicylamide where the hydroxy moiety of the salicyl group has been protected to prevent reaction of the hydroxy moiety. The term xe2x80x9cactivated salicylamidexe2x80x9d is defined herein as a salicylamide where the nitrogen atom of the amide group has been activated so that the nitrogen atom is in a more reactive condition, i.e., more prone to reaction.
Suitable protected/activated salicylamides include, but are not limited to, compounds having the formula 
where
R1, R2, R3, and R4 are independently hydrogen; halogen; C1-C4 alkoxy, optionally substituted with xe2x80x94OH or F; xe2x80x94OH; C1-C4 alkyl, optionally substituted with xe2x80x94OH or F; xe2x80x94COOH; xe2x80x94OC(O)CH3; xe2x80x94SO3H; nitrile; or xe2x80x94NR9R10;
R9 and R10 are independently hydrogen, C1-C4 alkyl, or oxygen;
R5 is a protecting group;
R6 is an activating group; or
R5 and R6 are combined to form a cyclic group, i.e., R5 and R6 form a single group that forms a heterocycle with the oxygen atom and nitrogen atom of the amide moiety.
Preferred halogens for R1, R2, R3, and R4 are chlorine, bromine, and fluorine. Preferred alkoxy groups for R1, R2, R3, and R4 include, but are not limited to, methoxy and ethoxy.
Suitable protecting groups include, but are not limited to, xe2x80x94C(O)CH3; xe2x80x94C(O)F3; xe2x80x94S(O)2CH3; xe2x80x94S(O)2CF3; benzyl; silyl; tetrahydropyranyl; and methylenealkoxy, such as methylenemethoxy and methyleneethoxy. Suitable activating groups include, but are not limited to, xe2x80x94C(O)CH3; xe2x80x94C(O)CF3; xe2x80x94S(O)2CH3; and xe2x80x94S(O)2CF3. Preferably, R5 and R6 are combined to form a cyclic group which protects the hydroxy moiety and activates the nitrogen atom of the amide moiety. More preferably, combined R5 and R6 are xe2x80x94C(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94.
Preferred protected/activated salicylamides include, but are not limited to, carsalam and derivatives thereof having the formula 
where R1, R2, R3, and R4 are defined as above.
Carsalam has the formula 
Carsalam may be prepared by methods known in the art, such as those described in Shapiro et al., JACS, 79:2811 (1957), and D. N. Dhar, A. K. Bag, Indian J. Chem., 21B:266 (1982). The aforementioned carsalam derivatives may be prepared by methods known for preparing carsalam substituting appropriate starting materials. These carsalam derivatives may also be prepared by adding the appropriate substituents to carsalam by methods known in the art.
One method of preparing the protected/activated salicylamide of the present invention comprises protecting the hydroxy moiety of a salicylamide and activating the amide moiety of the salicylamide. The protecting and activating steps may be performed in any order, but are preferably performed simultaneously. For example, the protecting step may be performed before performing the activating step.
Suitable (unprotected and unactivated) salicylamides include, but are not limited to, those having the formula 
where R1, R2, R3, and R4 are defined as above.
The hydroxy moiety of the salicylamide may be protected by methods known in the art. For example, the hydroxy moiety may be protected by reacting the salicylamide with a protecting agent, such as an activated halide. The resulting salicylamide has a protecting group attached to the oxygen atom of the hydroxy moiety. Examples of activated halides include, but are not limited to, acyl halides; silyl halides, such as silyl chlorides; benzyl halides; and methylene alkoxy halides, such as methylene methoxy halides and methylene ethoxy halides. Preferably, the reaction with an activated halide is performed in the presence of a base, such as potassium carbonate, triethylamine, or pyridine.
Another example of a protecting agent is an activated ether. Examples of activated ethers include, but are not limited to, dihydropyranyl ether. Preferably, the activated ether is reacted with the salicylamide under acid catalysis conditions, such as with sulfuric acid, paratoluene sulfonic acid, or camphor sulfonic acid in methylene chloride, tetrahydrofuran, or toluene.
The amide moiety of the salicylamide may be activated by methods known in the art. For example, the amide moiety may be activated by reacting the salicylamide with an activating agent, such as an acyl halide, acyl anhydride, sulfonyl halide, or sulfonyl anhydride. The resulting salicylamide has an activating group attached to the nitrogen atom of the amide moiety. Suitable acyl halides include, but are not limited to, those described above for protecting the hydroxy moiety of the salicylamide. Preferably, the activating agent is reacted with the salicylamide in the presence of a base, such as potassium carbonate, triethylamine, or pyridine.
The protecting and activating groups may be the same or different. The protecting and activating groups may be separate moieties (each attached to one of the hydroxy or amide moieties) or a single moiety (attached to both the hydroxy and amide moieties).
In the preparation of carsalam and the aforementioned derivatives thereof, the protecting and activating steps are typically performed simultaneously and the protecting and activating groups are a single group attached to both the hydroxy and amide moieties. One method of preparing carsalam and the derivatives thereof is by reacting the corresponding (unprotected and unactivated) salicylamide with an alkyl chloroformate, such as ethyl chloroformate; a phenyl chloroformate; or an imidazole alkoxy carbonyl.
The protected/activated salicylamide may be alkylated by the methods known in the art for alkylating phthalimide to form a primary amine. Sec, for example, Gibson and Bradshaw, Angewandte Chemie, International Edition in English, 7:919-930 (1968). The protected/activated salicylamide is substituted for the phthalimide in these methods.
The protected/activated salicylamide may also be alkylated by reacting the protected/activated salicylamide with an alkylating agent. The alkylating agent reacts with the nitrogen atom of the amide moiety of the salicylamide. The alkylating agent may be any known in the art, such as compounds of the formula
Xxe2x80x94R7xe2x80x94R8
where
R7 is a linear or branched, C1-C20 alkylene, alkenylene, or alkynylene;
R7 is optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, oxygen, nitrogen, sulfur, halogen, xe2x80x94OH, C1-C4 alkoxy, aryl, heteroaryl, or vinyl;
R7 is optionally interrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur;
R8 is carboxyl or a salt thereof, carboxylate, nitrile, halogen, ester, amine or salt thereof, alcohol, or thiol; and
X is a suitable leaving group. Suitable leaving groups include, but are not limited to, halogens, such as chlorine and bromine, and alcohols. Two preferred leaving groups are chlorine and bromine.
R7 may be substituted with an alkoxy moiety, such as methoxy or ethoxy. Preferably, R7 is xe2x80x94(CH2)nxe2x80x94 where n is an integer from about 1 to about 12, more preferably from about 7 to about 9, and most preferably about 7.
R8 is preferably a carboxyl or a salt thereof. Salts include, but are not limited to, organic and inorganic salts, for example, alkali-metal salts, such as sodium, potassium and lithium; alkaline-earth metal salts, such as magnesium, calcium or barium; ammonium salts; basic amino acids, such as lysine and arginine; and organic aminos, such as dimethylamine and pyridine. More preferably, R8 is a sodium salt of carboxyl.
In a preferred embodiment, R1, R2, R3, and R4 of the protected/activated salicylamide are hydrogen and R7 of the alkylating agent is xe2x80x94(CH2)7xe2x80x94 or xe2x80x94(CH2)9xe2x80x94. According to another preferred embodiment, R1, R2, and R4 of the protected/activated salicylamide are hydrogen, R3 is chlorine, and R7 of the alkylating agent is xe2x80x94(CH2)3xe2x80x94 or xe2x80x94(CH2)7.
The reaction between the alkylating agent and the protected/activated salicylamide is preferably carried out in the presence of a slight molar excess of protected/activated salicylamide relative to alkylating agent. Generally, the molar ratio of protected/activated salicylamide to alkylating agent ranges from about 1:1 to about 1:0.5, preferably from about 1:0.8 to about 1:0.99, and most preferably about 1:0.95.
The alkylating reaction is preferably performed in the presence of a suitable base, such as pyridine, triethylamine, diisopropylethylamine, sodium or potassium bicarbonate, sodium or potassium carbonate, or any combination of any of the foregoing. Preferably, the base is sodium carbonate. The reaction may be carried out in solvents, such as dimethylacetamide and dimethylformamide.
The alkylating reaction is generally performed at a temperature of from about 20 to about 100xc2x0 C. The reaction is preferably performed at a temperature of from about 50 to about 80xc2x0 C. and most preferably at about 70xc2x0 C. The reaction is generally performed for a time sufficient to ensure the complete reaction of the protected/activated salicylamide. The reaction duration varies depending on the starting materials. Generally, the reaction is allowed to run for a time sufficient so that at least about 90% and preferably 99% of the limiting, reagent, i.e., the alkylating agent, has been consumed, but is stopped before significant side reaction product build up. This reduces or eliminates the need for purification of the final product. Preferably, it is performed for from about 2 to about 18 hours, more preferably from about 3 to about 5 hours, and most preferably about 4 hours.
The alkylation reaction may be performed with alcohols under Mitsunobu conditions. See Mitsunobu, W. and Sano, J., J. Amer. Chem. Soc., 94:674 (1972). Such alkylation reactions are performed in the presence of triphenylphosphene (PPh3) and dialkyl azodicarboxylates, such as diisopropyl azodicarboxylate (DIAD). The products of this reaction may be hydrolyzed to the corresponding alkylated salicylamides.
The protected/activated alkylated salicylamide is then deprotected and deactivated to yield the alkylated salicylamide. Typically, this step entails the removal of the protecting and activating groups from the salicylamide. The protecting and activating groups may be removed by acidic, basic and/or neutral hydrolysis as known in the art.
Phenolic protecting groups, except for acylated phenolic protecting groups, may be removed by acidic hydrolysis. Acidic hydrolysis may be performed, for example, with aqueous hydrochloric acid or aqueous trifluoroacetic acid. Acylated phenolic protecting groups generally are removed by basic hydrolysis.
The activating groups may be removed from the amide moiety by basic hydrolysis. Basic hydrolysis may be performed, for example, with aqueous sodium carbonate or aqueous sodium hydroxide.
Neutral hydrolysis may be performed, for example, with super-heated water at a temperature of from about 100 to about 250xc2x0 C.
The deprotecting and deactivating step may be performed at a temperature of from about 20 to about 100xc2x0 C. and preferably from about 90 to about 100xc2x0 C.
Suitable solvents for the protected/activated alkylated salicylamide in the deprotecting and deactivating step include, but are not limited to, water, ethanol, and any combination of any of the foregoing.
When the protected/activated salicylamide is carsalam or a derivative thereof, the alkylated salicylamide may be deprotected and deactivated by hydrolysis. This causes the bonds between the carbonyl group and the adjacent oxygen atoms to cleave, thereby deprotecting the hydroxyl moiety. Hydrolysis may be carried out under conditions known in the art. For example, basic hydrolysis may be performed with an alcoholic solvent, such as ethanol.
After hydrolysis of the carsalam or carsalam derivative, the activated salicylamide may be deactivated by methods known in the art. For example, hydrochloric acid may be added to the activated alkylated salicylamide until the pH of the reaction mixture is less than about 4. This causes the bond between the carbonyl moiety and the nitrogen atom of the amide moiety of the salicylamide to cleave and release carbon dioxide.
Optionally, the alkylated salicylamide may be further reacted to modify the end group of the alkylating moiety, i.e., R8. For example, the end group xe2x80x94CN or xe2x80x94C(O)Oxe2x80x94CH2xe2x80x94CH3 may be modified to xe2x80x94COOH or a salt thereof. This may be accomplished by methods known in the art, such as acidic and basic hydrolysis.
The present method may be used to prepare alkylated salicylamides having the formula 
where R1, R2, R3, R4, R7, and R8 are defined as above.
The alkylated salicylamides of the present invention may be purified by recrystallization or fractionation on one or more chromatographic supports. Fractionation may be performed on suitable chromatographic supports, such as silica gel or alumina, using solvent mixtures such as acetic acid/butanol/water as the mobile phase; reverse phase column supports using trifluoroacetic acid/acetonitrile mixtures as the mobile phase; and ion exchange chromatography using water as the mobile phase. The alkylated salicylamides may also be purified to remove impurities, such as inorganic salts, by extraction with a lower alcohol, such as methanol, butanol, or isopropanol.
The method of the present invention uses readily available and inexpensive starting materials and provides a cost-effective method for preparing and isolating alkylated salicylamides. The method is simple to perform and is amenable to industrial scale-up for commercial production.